CN110678506A - 防止生物膜形成 - Google Patents

防止生物膜形成 Download PDF

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Publication number
CN110678506A
CN110678506A CN201880021807.XA CN201880021807A CN110678506A CN 110678506 A CN110678506 A CN 110678506A CN 201880021807 A CN201880021807 A CN 201880021807A CN 110678506 A CN110678506 A CN 110678506A
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CN
China
Prior art keywords
bpei
layer
coating
negatively charged
glyoxal
Prior art date
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Pending
Application number
CN201880021807.XA
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English (en)
Inventor
A·卡恩
J·赫德里克
M·费弗雷
T·范凯塞尔
薛沛芸
H·德利吉安尼
R·沃杰特基
N·帕克
杨义燕
丁鑫
连振昌
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institute of Bioengineering and Nanotechnology
International Business Machines Corp
Original Assignee
Institute of Bioengineering and Nanotechnology
International Business Machines Corp
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Filing date
Publication date
Application filed by Institute of Bioengineering and Nanotechnology, International Business Machines Corp filed Critical Institute of Bioengineering and Nanotechnology
Publication of CN110678506A publication Critical patent/CN110678506A/zh
Pending legal-status Critical Current

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Abstract

本文描述了抗菌涂层和制备抗菌涂层的方法。形成第一支化聚乙烯亚胺(BPEI)层，并在BPEI层的表面上形成第一乙二醛层。将第一BPEI层和第一乙二醛层固化以形成交联的BPEI涂层。可以用超疏水部分、超亲水部分或带负电的部分修饰第一BPEI层，以增加涂层的防污特性。可以用接触灭杀性杀菌部分修饰第一BPEI层，以增加涂层的杀菌特性。

Description

防止生物膜形成
技术领域
本发明一般涉及用于预防和处置涉及可植入医疗器械的细菌和微生物定植、生物膜形成和感染的抗菌涂层。更具体地，本发明涉及用于形成化学改性和交联的支化聚乙烯亚胺(BPEI)涂层的系统和方法。本发明还涉及用于形成带负电的聚合物涂层的系统和方法。本发明还涉及用电极使器件表面带负电的系统和方法。
背景技术
微生物在湿润表面上的积聚，或曰生物污损，是诸如医疗器械、海洋仪器、食品加工、甚至家用排水管等广泛应用中的材料的普遍存在的问题。通常，细菌通过形成生物膜而引发生物污染，生物膜由高度有序的粘附集落形成，最常见于自生的细胞外聚合物质基底内。
可植入器械(例如假体关节、心脏瓣膜、人造心脏、血管支架和移植物、心脏起搏器和除颤器、神经刺激装置、胃起搏器、血管导管和端口(例如Port-A-Cath))的使用在增长，由于先进的治疗方法，免疫受损患者的数量也在增长。感染是可植入医疗器械的问题。植入材料和装置的表面代表免疫受损的局部区域，其中的细菌定植和随后的生物膜形成，难以诊断和处置。生物膜是持续感染的罪魁祸首，因为它们具有抗治疗性，潜在地释放有害毒素，以及易于扩散微生物，这可能导致它们在其上生长(例如导管阻塞)或化脓的播种微生物的可植入器械的故障。
诸如从患者身体移除受感染的植入器械的极端措施，通常是唯一可行的管理选择。尽管在手术过程中使用消毒技术和预防性抗生素治疗来预防定植，但这种做法在预防围手术期细菌定植方面并非100％有效。此外，假体关节上细菌定植的风险，在假体关节植入后很长时间内都存在。例如，对于金黄色葡萄球菌菌血症，假体关节上定植的风险接近25％。
消除与可植入物质和装置相关的定植和感染的抗生素治疗，在根除这些过程中涉及的细菌和真菌的能力方面受到限制。这有多种原因，包括由于扩散有限而导致生物膜深处的抗生素浓度降低，一般抗生素无法消除“最后的”病原体细胞(通常由免疫系统完成，对于可植入器械的情形却不能很好地起作用)，并且微生物能够持续存在，即变得无代谢活性并因此在功能上对抗生素具有相对耐药性。抗生素抗性使治疗与器械相关的感染更具挑战性。事实上，导致装置相关感染的微生物(例如肠球菌、葡萄球菌)经常遇到抗生素耐药性。
因此，近年来为开发抗菌表面投入了相当大的努力。这些表面可分为两类：(i)防止微生物粘附的防污表面和(ii)引发细菌灭杀的杀菌表面。设计抗菌表面的典型策略包括表面的超分子(非共价)涂层或表面的改性(即化学改性或结构化)。通过掺入α,ω-二氨基功能化的聚(乙二醇)(PEG，摩尔质量为4,600g/mol)，以增加亲水性以抵抗细菌附着，可以获得防污性能，同时通过可释放的诸如如银纳米粒子(Ag NPs)和抗生素的细菌杀灭物质的功能化，或通过带有像季铵盐的接触灭杀性杀菌块的装饰，可以获得杀菌特性。然而，目前的技术遭受长期抗菌性能和稳定性差、细菌耐药性的不良发展或产业环境的有限可扩展性的困扰。
发明内容
本发明涉及用于形成用电极来预防和处置细菌和微生物定植、生物膜形成、以及感染的化学改性和交联的支化聚乙烯亚胺(BPEI)涂层、带负电的聚合物涂层和带负电的器械表面的系统和方法。
在一些实施例中，将BPEI用作附着疏水或亲水部分的载体，以改善最终材料的抗微生物/防污性能。将BPEI和乙二醛的水溶液依次喷涂在基底上，并在固化后提供交联涂层，该涂层提供了用于将抗微生物材料经济和大规模地应用于医疗器械的通用技术平台的优点。
在一些实施例中，BPEI用具有负表面电荷的材料改性。以这种方式形成的涂层排斥否则将粘附到可植入器械表面的细菌。可以用相同的技术来防止诸如内窥镜、腹腔镜、内窥镜的医疗设备和医疗系统中(例如患者环境中)表面的定植。
根据本发明的一个或多个实施例，提供了一种形成交联的BPEI涂层的方法。该方法包括在基底上形成第一BPEI层。在第一BPEI层的表面上形成第一乙二醛层。在可操作的温度下固化第一BPEI层和第一乙二醛层以形成交联的BPEI涂层。该涂层提供了用于经济和大规模地将防污和杀菌材料应用于可植入和非可植入医疗器械的表面的通用技术平台的技术益处。
可以用超疏水部分(moieties)、超亲水部分、带负电的部分或前述的组合来修饰第一BPEI层，以提供具有改善的防污特性的涂层的技术益处。可以用接触灭杀杀菌部分修饰第一BPEI层，以提供具有改善的杀菌特性的涂层的技术益处。
根据本发明的一个或多个实施例，提供了用于预防和处置细菌和微生物定植、生物膜形成和感染的装置。该装置包括可植入医疗器械和在该可植入医疗器械的表面上形成的乙二醛交联的BPEI涂层。乙二醛交联的BPEI涂层的胺与超疏水部分或带负电的部分共价键合，以提供具有改进的防污特性的涂层的技术益处。
根据本发明的一个或多个实施例，提供了一种形成带负电的聚合物涂层的方法。该方法包括提供聚合物并以具有负Zeta电位的生物相容性部分功能化所述聚合物。在一些实施例中，聚合物是羟基磷灰石或聚(3,4-亚乙二氧基噻吩)(PEDOT)，生物相容性部分是羧酸基团或聚苯乙烯磺酸盐基团。以这种方式，提供了具有负表面电荷的涂层的技术益处。
根据本发明的一个或多个实施例，提供了用于预防和处置细菌和微生物定植、生物膜形成和感染的装置。该装置包括可植入医疗器械和形成在可植入医疗器械表面上的带负电涂层。带负电涂层提供具有改进的抗微生物特性的涂层的技术益处。在一些实施例中，将电源嵌入可植入医疗器械内，以提供用于维持带负电涂层的独立装置的技术益处。可以通过局部pH的变化或体温的升高来触发电源以维持带负电涂层，以提供具有仅在必要时触发的有效电源的可植入医疗器械的技术益处。
可应用本发明涂层的可植入医疗器械包括但不限于假体关节、血管线、支架或移植物、静脉过滤器、牙齿植入物、耳蜗植入物、用于骨折内固定的金属、导尿管、脑室腹腔分流器、心脏或神经起搏器、心脏瓣膜或心室辅助装置。
通过以下结合示出本发明的实施例和各方面的附图的描述，本发明的其他优点和功能将变得显而易见。
附图说明
现在将参考附图，仅通过示例的方式描述本发明的实施例，附图中：
图1描绘了根据本发明的一个或多个实施例的具有在制造BPEI涂层的方法的中间操作期间在基底上形成的第一BPEI层的结构的横截面图；
图2描绘了根据本发明的一个或多个实施例的在制造BPEI涂层的方法的中间操作期间固化第一BPEI层和第一乙二醛层以形成均匀和乙二醛交联的涂层之后的结构的横截面图；
图3描绘了根据本发明的一个或多个实施例形成的均相和乙二醛交联涂层的差示扫描量热法(DSC)痕迹；
图4描绘了根据本发明的一个或多个实施例的在制造具有带负电表面的可植入医疗器械的方法的中间操作期间由带负电涂层涂覆的假体髋关节；
图5描绘了应用于玻璃(对照)和根据本发明一个或多个实施例形成的PEI基涂层的金黄色葡萄球菌(SA)和铜绿假单胞菌(PA)的一(1)天培养XTT测定(A,B)；和
图6描绘了应用于玻璃(对照)和根据本发明的一个或多个实施例形成的PEI基涂层的七(7)天SA培养XTT测定(A)。
具体实施方式
本文参照相关附图描述了本发明的各种实施例。在不脱离本发明的范围的情况下，可以设计可替代的实施例。注意，在以下描述和附图中，规定了元件之间的各种连接和位置关系(例如上方、下方、相邻等)。除非另有说明，这些连接和/或位置关系可以是直接的或间接的，并且本发明并非有意在这方面进行限制。因此，实体的耦合可以指直接或间接耦合，并且实体之间的位置关系可以是直接或间接的位置关系。作为间接位置关系的示例，本说明书中提及的在层“B”上形成层“A”，包括有一个或多个中间层(例如层“C”)在层“A”和层“B”之间的情况—只要层“A”和层“B”的相关特性和功能基本上不被该中间层改变。
以下定义和缩写将用于解释权利要求和说明书。如这里所使用的，术语“包括”、“包含”、“具有”、“含有”、“有”或其任何其他变型旨在涵盖非排他性的包容。例如，包含一系列元素的组合物、混合物、过程、方法、物品或装置不一定仅限于那些元素，而是可以包括未明确列出的其他元素或这种组合物、混合物、过程、方法物品或装置方法固有的元素。
另外，术语“示例性”在本文中用于表示“用作示例、实例或说明”。本文中描述为“示例性”的任何实施例或设计不必被解释为相比其它实施例或设计是优选的或有利的。术语“至少一个”和“一个或多个”应理解为包括大于或等于1的任何整数，即一、二、三、四等。术语“多个”应理解为包括大于或等于2的任何整数，即二、三、四、五等。术语“连接”可以包括间接“连接”和直接“连接”。
说明书中提及的“一个实施例”、“实施例”、“示例实施例”等，指示所描述的实施例可以包括某特定特征、结构或特性，但是每个实施例可以或可以不是包括该特定特征、结构或特性。而且，这种短语不一定是指同一实施例。此外，当结合实施例描述某特定特征、结构或特性时，结合无论是否明确描述的其他实施例影响这样的特征、结构或特性被认为是在本领域技术人员的知识范围之内。
出于以下描述的目的，术语“上”、“下”、“右”、“左”、“垂直”、“水平”、“顶部”、“底部”及其派生词应涉及如附图中的方位所示的所描述的结构和方法。术语“覆盖”、“顶上”、“在顶部”，“定位在…上”或“定位在顶部”意味着第一元件—例如第一结构—存在于第二元件—例如第二结构—之上，其中在第一元件和第二元件之间可以存在诸如界面结构的中间元件。短语“直接接触”意味着第一元件(例如第一结构)和第二元件(例如第二结构)在两个元件的界面处没有任何中间导电、绝缘或半导体层的情况下连接。短语“对…是选择性的”—例如“对第二元件是选择性的第一元件”，意味着第一元件可以被蚀刻，第二元件可以用作蚀刻停止。术语“共形”(例如，共形层)是指层的厚度在所有表面上基本相同，或者厚度变化小于层的标称厚度的15％。
如本文所使用的，术语“约”、“基本上”、“大约”及其变体旨在包括与基于提交本申请时可用设备的特定量的测量相关联的误差程度。例如，“约”可以包括给定值的±8％或±5％、或±2％的范围。
现在转向与本发明更具体相关的技术的描述，如本文先前所述，利用防污或杀菌表面的常规抗菌材料的长期抗菌性能和稳定性差，细菌耐药性不良发展，对产业环境可扩展性有限。此外，虽然细菌细胞在杀生物剂功能化表面上的裂解降低了生物膜形成的速率，但是希望结合防污和杀菌性能以确保表面的长期功效。
在抗微生物材料中，聚乙烯亚胺(PEI)代表了常规材料的有趣替代物。PEI在市场上有售，具有可用于附着功能组的季/仲/伯胺，并且被认为以接触灭杀方式杀死细菌(即不需要从表面释放毒性部分)。已经广泛研究了PEI的化学改性使其更加疏水和/或附着永久电荷的可能性。通过还原胺化或亲核取代交联的PEI纳米颗粒是有效的抗微生物剂。然而，用于掺入PEI抗微生物材料的常规方法需要多步修改程序，依赖于苛刻、对环境不友好的处理，和/或缺乏适用于产业环境的可扩展沉积方法。此外，当用作涂层时，PEI与大多数抗菌材料一样，长期功效较差。
因此，仍然需要一种环境友好的方法，使用组合的抗微生物/防污策略来防止生物膜形成，从而长时间保护表面和装置。因此，本发明所针对的正是解决这个和其他需求。
下面参照图1-6中的附图详细描述本发明各实施例的用于形成化学改性和交联的BPEI涂层、带负电的聚合物涂层和带负电的器械表面的示例方法，其使用电极来预防和处置细菌定植、生物膜形成或感染以及由此产生的结构。
在一些实施例中，支化的PEI(BPEI)在基底表面用其可用的与乙二醛反应的伯胺交联化。伯胺与乙二醛的反应可以产生如下的方案1中所示的产物(即α-羟胺1、亚胺2和4/1加合物3)的混合物：
Figure BDA0002217414710000071
每种产物的出现取决于胺的性质、化学计量、溶剂和温度。在室温(RT)下通过核磁共振光谱(NMR)进行分析的模型研究中，观察到的主要产物是亚胺2。然而，在改变化学计量的同时，观察到可归因于存在3的其他产物的痕迹。此外，将PEG与0.5当量乙二醛在N-甲基吡咯烷酮(NMP)中混合可在大约四(4)小时后使反应混合物凝胶化，证明3的形成，可能在网络中被动力学淬灭。
在一些实施例中，BPEI和乙二醛都是从水中沉积的。有益的是，该方法允许更环保的过程。最有趣的是，BPEI与乙二醛的反应非常快，当混合浓度大于约25％(重量)的BPEI的水溶液和浓度大于约5％(重量)的乙二醛的水溶液时，导致反应介质立即凝胶化。利用这种快速凝胶化，可以实现逐层的过程。
图1示出了根据一个或多个实施例的具有在制造BPEI涂层的方法的中间操作期间在基底104上形成的第一BPEI层102的结构100的截面图。所述BPEI层102足够粘稠以允许良好地覆盖基底表面。在第一BPEI层102的表面上形成第一乙二醛层106。可以使用任何合适的工艺在基底104上形成或沉积第一BPEI层102和第一乙二醛层106，例如通过浸涂或喷涂。在一些实施例中，将第一BPEI层102和第一乙二醛层106从位于基底104上方约15厘米的距离的喷嘴以约25psi的压力连续喷射到基底104(例如APTES功能化的玻璃基底)上。
可以以类似的方式在结构100上形成BPEI和乙二醛的另外的交替层。可以根据最终涂层的所需厚度来选择所沉积的层的总数。在一些实施例中，结构100由单层BPEI和乙二醛(总共2层)形成。在一些实施例中，使用四(4)或九(9)层，但是其他厚度(因此总层数)在本发明的预期范围内。在一些实施例中，取决于BPEI层的浓度、乙二醛层的浓度和温度(例如，对于约20摄氏度的温度下、具有大于约25％(重量)的BPEI和5％(重量)乙二醛的溶液)，可以观察到立即凝胶化。
在一些实施例中，BPEI层(例如第一BPEI层102)和乙二醛层(例如第一乙二醛层106)从22ml的储液器的喷枪沉积在基底104上。在一些实施例中，将重量百分比为2.5％的乙二醛水溶液转移到第一个喷枪的22ml储液器中，将6.8g MilliQ水中的PEI(1.8k摩尔质量，含0.31mmol或3.19mmol-NH2部分)转移到第二个喷枪22ml储液器中。在一些实施例中，在喷涂工艺之后，可以将基底104转移到热板上以进行固化。
图2示出了根据一个或多个实施例在制造BPEI涂层的方法的中间操作期间固化第一BPEI层102和第一乙二醛层106以形成均匀和乙二醛交联的涂层200(下文中称为“涂层200”)之后的结构100的横截面图。在一些实施例中，将第一BPEI层102和第一乙二醛层106在约30摄氏度的温度下固化约1小时。在一些实施例中，将第一BPEI层102和第一乙二醛层106在约30至约120摄氏度的逐渐升高的温度下固化约1小时内。在一些实施例中，将BPEI层102和第一乙二醛层106在约120摄氏度的温度下固化约1小时。在一些实施例中，使用三阶段热处理来固化：(1)第一阶段在30摄氏度的温度下固化1小时；(2)第二阶段在约30摄氏度至约120摄氏度的逐渐升温的温度下固化超过1小时；(3)第三阶段在约120摄氏度的温度下固化1小时。然后使基底104冷却至室温。固化涂层200允许除去水(或任何残留溶剂)并确保最大交联密度。
通过改变乙二醛与伯BPEI胺的量，可以改变最终涂层的交联密度和性质(玻璃化转变温度(Tg)、耐水性等)，图2中所示的差示扫描量热法(DSC)迹线证明了这一点。例如，将乙二醛的量从0.5当量增加到2当量，相对于表现出1,800g/mol摩尔质量的BPEI的伯胺的量，导致Tg升高135摄氏度。
涂层200可以被选择性地形成或改性以增加其防污和杀菌性能。例如，通过在与超疏水、超亲水或带负电的部分固化之前或期间共价连接或功能化BPEI层(例如第一BPEI层102)，通过用诸如银纳米颗粒(Ag NPs)和抗生素的可释放杀菌物质功能化BPEI层(例如第一BPEI层102)，或者通过掺入如季铵盐(例如接触灭杀性阳离子聚合物)那样的接触灭杀性杀菌部分，可以获得防污性能。
在一些实施例中，第一BPEI层102的胺在固化之前与部分共价键合。这个反应可导致超疏水性(如方案2中所示的)或带负电的部分(如方案3中所示)的掺入。
方案2:
Figure BDA0002217414710000091
方案3:
Figure BDA0002217414710000092
在一些实施例中，疏水性、超亲水性或带负电的部分通过与乙二醛的反应分别掺入到涂层200中，如方案4、5和6中所示。在方案5中，例如，α,ω-二氨基-(Mn＝4,600g/mol)和α-甲氧基、ω-氨基-(Mn＝2,000g/mol)功能化的PEG，通过在固化过程中与乙二醛的反应而以化学方式被掺入BPEI/乙二醛混合物中。
方案4:
Figure BDA0002217414710000101
方案5:
Figure BDA0002217414710000102
方案6:
Figure BDA0002217414710000103
在一些实施例中，第一BPEI层102用在水溶液中的阳离子聚合物部分功能化。以这种方式，涂层200被改性，具有杀菌特性(即涂层200的杀菌特性由第一BPEI层102的胺引起，其在水溶液中部分带正电)。在一些实施例中，阳离子部分可通过季铵化而永久带电。在一些实施例中，第一BPEI层102的胺被卤代烷烃或卤代芳基季铵化。
在一些实施例中，可以通过修饰基底104或通过添加粘合促进剂部分来促进涂层200在基底104上的粘附。例如，在一些实施例中，可以通过(3-氨基丙基)三乙氧基硅烷(APTES)的缩合用-NH2部分功能化基底104的表面。附着在基底表面的胺部分在固化过程中与乙二醛反应。在一些实施例中，将含有儿茶酚的部分加入到BPEI/乙二醛混合物中的任一种或两种中，以促进涂层200与基底104的粘附。
图5描绘了分别应用于玻璃(对照)和根据本发明一个或多个实施例形成的PEI基涂层的金黄色葡萄球菌(SA)和铜绿假单胞菌(PA)的一(1)天培养XTT测定(A,B)。选择金黄色葡萄球菌(SA)和铜绿假单胞菌(PA)来评估PEI基涂层的抗微生物/防污性能，是因为它们分别是革兰氏阳性和革兰氏阴性细菌，已知它们是导致医院感染的原因。SA和PA都能够在对照未改性的玻璃基底上定殖。特别地，在培养仅一(1)天后，就在玻璃表面上检测到致密的SA层。可以使用已知技术制备玻璃基底。例如，可将3"×2"的玻璃显微镜载玻片浸入表面活性剂溶液中过夜。然后可以用水和乙醇冲洗载玻片并干燥。然后可以通过UV/臭氧处理载玻片15分钟。然后将这些干净的载玻片浸入10％APTES的乙醇溶液中30分钟，并在干燥前用乙醇彻底冲洗。可以安装铝带(例如80μm厚)边界，并且可以在喷涂之前将载玻片保持在氮气下。
在用功能性PEI/乙二醛涂覆后，大多数表面显示出一些防污活性。例如，与对照玻璃基底相比，未改性的BPEI涂层(BPEI)显著地将SA和PA的结垢分别降低至11％和25％。用PEG功能化的BPEI(1，用亲水性NH2-PEG4.6k-NH2和mPEG2k-NH2)涂覆没有改善对SA的防污活性。这可以由PEG/BPEI和未改性BPEI涂层的类似表面亲水性来解释。此外，1涂层对PA具有较低的防污活性，可能是因为PEG链屏蔽了BPEI的阳离子电荷，从而降低了BPEI的抗菌效力。
使用带负电的谷氨酸(2a，用NH2-PEG4k-NH2/带负电的谷氨酸功能化的BPEI)、天冬氨酸(2b，用NH2-PEG4k-NH2/带负电的天冬氨酸功能化的BPEI)、和羧酸丙烯酸酯(2c，用NH2-PEG4k-NH2/带负电的羧酸丙烯酸酯功能化的BPEI)形成BPEI涂层，应静电排斥带负电的细菌。然而，发现2a和2b涂层显示出与未改性BPEI涂层同样良好的防污活性。虽然带负电的部分可能会排斥细菌，但涂层的总电荷减少了，这可能导致BPEI的抗菌作用降低。
发现以增加疏水性而氟化的BPEI涂层成功地增加涂层的表面疏水性，接触角高达76°(3a，用CF3-CF2-的疏水氟化部分功能化的BPEI)和73°(3b，用CF3-(CF2)5-的疏水氟化部分功能化的BPEI)。然而，与未改性的BPEI表面相比，这些涂层上的SA和PA结垢增加，可能是由于在部分取代BPEI胺以安装氟化部分后阳离子电荷含量降低。
在1天培养测试中显示出有希望的结果的PEI基涂层(BPEI、1、2a、2b和2c，如图5中所示)的长期抗微生物/防污活性与SA一起培养7天。图6描绘了应用于玻璃(对照)和PEI基涂层BPEI、1、2a、2b和2c的七(7)天SA培养XTT测定(A)。生长培养基(medium)每天更换为新鲜培养基。所有BPEI基薄膜在与SA一起培养7天后保持完整。XTT和活/死染色结果证明PEI基涂层BPEI、1、2a、2b和2c在7天后表现出优异的防污活性，细菌计数与培养1天后观察到的相当(如图6所示)，无论改性策略如何。
已经描述了用于改变涂层200的防污和杀菌特性的各种方案。应当理解，这些方案仅仅代表所有可用的方案，其他类似的方案可以用于修饰涂层200。通过平衡涂层的疏水性或亲水性与涂层与活/死细菌的静电吸引或排斥，可以优化抗菌涂层的长期稳定性和功效。
在一些实施例中，形成带负电的聚合物涂层以预防和处置细菌和微生物定植、生物膜形成和涉及可植入医疗器械的感染。在一些实施例中，通过用具有负Zeta电位的生物相容性材料功能化市场销售的聚合物来制备涂层200。在一些实施例中，例如，涂层200是用羧酸COO-阴离子基团(例如十二烷二酸)功能化的羟基磷灰石。在一些实施例中，涂层200是用聚苯乙烯磺酸盐基团功能化的聚(3,4-亚乙二氧基噻吩)(PEDOT)。这些反应可导致如下的方案7中描述的示例性涂层：
Figure BDA0002217414710000131
在一些实施例中，用电极对装置(即可植入医疗器械)的表面充负电，以预防和处置细菌和微生物定植、生物膜形成和感染。图4描绘了根据一个或多个实施例的在制造具有带负电的表面的可植入医疗器械的方法的中间操作期间由带负电涂层502涂覆的假体髋关节500。为了便于说明，仅描绘了单个医疗器械(例如假体髋关节500)。应当理解，各种医疗器械都可以以类似方式用电极充负电。在一些实施例中，医疗器械是假体心脏瓣膜、左心室辅助装置、血管支架、血管移植物、假体关节、骨植入物、植入的牙齿、植入的起搏器、起搏器发生器或导线、血管内线路、脑室腹腔分流术、导尿管、眼植入物、颅内植入物或皮下植入物。
在一些实施例中，涂层502的负电荷由电源504维持。电源504可以是用于可植入医疗器械的任何合适的电源，诸如通过电极连接连接到带负电涂层502的电池或微电容器。在一些实施例中，电源可以与可植入器械集成或功能性连接到可植入器械。在一些实施例中，可以使用电感、RFID或超声波通过无线发射器/接收器508从患者身体外部对电源充电。在一些实施例中，无线发射器/接收器508在功能上与包括数字电脑的控制单元510连接。在一些实施例中，带负电涂层502可以由能够从机械运动产生电能(电流)的纳米线网制成。以这种方式，带负电涂层502的移动使电源504充电。在一些实施例中，嵌入在假体髋关节500内的机械能变压器512从身体运动和电源504产生电能(电流)。在一些实施例中，控制单元510可以从患者身体外部无线地发送和接收数据。
在一些实施例中，涂层502的负电荷由潜在感染的指标的存在而触发，这些指标诸如是局部pH的变化(指示例如微生物代谢的结果)或体温上升(表示例如发烧)。在一些实施例中，涂层502的负电荷维持特定时期，诸如植入后的一段时间、全身感染后的一段时间、或由通过无线发射器/接收器508从远程位置(即位于身体外部的控制模块)接收的控制信号所确定的一段时间。
材料、制备和表征
乙二醛(重量浓度40％的水溶液)、天冬氨酸、乙醇酸、2-羧乙基丙烯酸酯和BPEI(Mn＝10,000g/mol)来自Aldrich。(3-氨基丙基)三乙氧基硅烷(APTES)来自Gelest。BPEI(Mn＝1,800g/mol)来自Jeffamine。D4000来自Hunstman。MeO-PEG2k-NH2来自PolymerScience，Inc。所有材料无需进一步纯化即可使用。使用已知方法制备NH2-PEG4.6k-NH2。金黄色葡萄球菌(ATCC No.6538)和铜绿假单胞菌(ATCC No.9027)来自ATCC。Mueller-HintonBroth(MHB)来自新加坡的BD。XTT盐(2,3-双(2-甲氧基-4-硝基-5-磺基-苯基)-2H-四唑-5-甲酰苯胺)来自Sigma Aldrich。LIVE/DEAD BacLight细菌活力试剂盒来自Thermofisher。
通过将3"×2"的玻璃显微镜载玻片浸入表面活性剂溶液中过夜来制备玻璃基底。然后将载玻片用水和乙醇冲洗并干燥。然后将载玻片用UV/臭氧处理15分钟。将干净的载玻片浸入10％APTES的乙醇溶液中30分钟，并在干燥前用乙醇彻底冲洗。安装铝带(例如80μm厚的)边界，并在喷涂之前将载玻片保持在氮气下。
在Q500上进行热重分析(TGA)。在N2气氛下，以5摄氏度/分钟的加热速率将样品(例如5至7mg)从室温扫描至500摄氏度。在TA Instruments Q2000上进行差示扫描量热法(DSC)分析。在铝封闭盘中以5摄氏度/分钟的加热速率将样品(例如5至7mg)从室温扫描至200摄氏度。使用双悬臂在TA Instruments DMA 2980上进行动态机械分析(DMA)。以每分钟5摄氏度的加热速率从-80摄氏度至200摄氏度获取样品(沉积在金属筛网上，约12×6×1mm)。
通过喷涂制备PEI-乙二醛薄膜的程序
将质量分数2.5％的乙二醛水溶液转移到第一喷枪的22mL储液器中。将6.8gMilliQ水中的0.563g PEI1.8k(0.31mmol或3.19mmol-NH2部分)第二溶液转移到第二喷枪的22mL储液器中。将这些层交替喷涂在APTES功能化的玻璃基底(以乙二醛溶液开始)上，在基底和喷嘴之间的距离为约15cm，喷嘴压力为约25psi，直至达到所需的总层数(例如共9层)。然后将玻璃基底转移到热板上进行固化。使用以下热处理：30摄氏度1小时，30摄氏度至120摄氏度1小时，120摄氏度1小时。固化后，使薄膜冷却至室温。用剃刀刀片从表面刮下一片薄膜用于热分析。或者，将相同的溶液喷涂在金属筛网上，通过DMA分析。
抗菌/防污性能的表征
将MHB培养基中的细菌金黄色葡萄球菌和铜绿假单胞菌(0.5mL、105CFU/mL)接种在48孔板中的样品表面(0.5cm×0.5cm)上。在培养24小时后，将样品用无菌PBS洗涤三次。然后通过XTT测定和活/死细菌染色评估抗微生物/防污性质。将XTT盐(2,3-双(2-甲氧基-4-硝基-5-磺基-苯基)-2H-四唑-5-甲酰苯胺)(50μL 1mg/mL)和甲萘醌(10μL，0.4mM)用PBS洗涤的样品在37摄氏度下培养4小时。通过TECAN酶标仪记录490nm处的吸光度。由于活细菌细胞将XTT转化为橙色甲臜,490nm处的吸收与表面上细菌的代谢活性相关。为了观察表面上的细菌，使用LIVE/DEAD Baclight细菌活力试剂盒对细菌进行染色。通过将1.5μL的每种染料原液添加到1mL PBS中来制备碘化丙锭(具有受损膜的染色细菌)和
Figure BDA0002217414710000151
9(具有完整膜的染色细菌)的染料溶液。通过与染料溶液(500μL)一起在黑暗中培养至少15分钟将PBS洗涤的样品染色。使用Zesis LSM共聚焦显微镜获得荧光图像。每天用新鲜的MHB培养基替换细菌生长培养基MHB，以评估长期抗微生物/防污性能。如上文详细描述的，在培养7天后进行XTT测定和活/死细菌染色。
已经出于说明的目的给出了对本发明的各种实施例的描述，但是所述描述并不旨在穷举或将本发明限制于所描述的实施例。在不脱离本发明的范围和精神的情况下，许多修改和变化对于本领域普通技术人员来说是显而易见的。本文中所用术语的选择，是为了最好地解释实施例的原理、实际应用或对市场中发现的技术的技术改进，或者使本领域普通技术人员能够理解本文所述的实施例。

Claims (25)

1.一种形成交联支化聚乙烯亚胺(BPEI)涂层的方法，该方法包括：
形成第一BPEI层；
在所述第一BPEI层的表面上形成第一乙二醛层；和
固化所述第一BPEI层和所述第一乙二醛层。
2.如权利要求1所述的方法，还包括在固化之前，在所述第一乙二醛层的表面上形成多个交替的BPEI层和乙二醛层。
3.如权利要求1所述的方法，还包括用疏水部分、超亲水部分、带负电的部分或前述的组合修饰所述第一BPEI层。
4.如权利要求1所述的方法，其中形成所述第一BPEI层包括用NH2-PEG4.6k-NH2或mPEG2k-NH2功能化所述第一BPEI层。
5.如权利要求1所述的方法，其中形成所述第一BPEI层包括用NH2-PEG4k-NH2和带负电的谷氨酸功能化所述第一BPEI层。
6.如权利要求1所述的方法，其中形成所述第一BPEI层包括用NH2-PEG4k-NH2和带负电的天冬氨酸功能化所述第一BPEI层。
7.如权利要求1所述的方法，其中形成所述第一BPEI层包括用NH2-PEG4k-NH2和带负电的羧酸丙烯酸酯功能化所述第一BPEI层。
8.如权利要求1所述的方法，其中形成所述第一BPEI层包括用疏水性氟化部分功能化所述第一BPEI层。
9.如权利要求8所述的方法，其中所述疏水性氟化部分包含CF3-CF2 or CF3-(CF2)5。
10.如权利要求1所述的方法，其中形成所述第一BPEI层包括将所述第一BPEI层从位于所述基底上方约15厘米的压力约25psi的喷嘴沉积到基底上。
11.权利要求1所述的方法，还包括用接触灭杀性杀菌部分修饰所述第一BPEI层。
12.如权利要求1所述的方法，其中所述接触灭杀性杀菌部分包括季铵盐。
13.如权利要求1所述的方法，还包括用阳离子聚合物部分修饰所述第一BPEI层。
14.如权利要求13所述的方法，还包括季铵化所述第一BPEI层的胺。
15.一种装置，该装置包括：
可植入医疗器械；和
在所述可植入医疗器械的表面上形成的乙二醛交联的支化聚乙烯亚胺(BPEI)涂层；
其中所述BPEI涂层的胺与超疏水部分或带负电部分共价键合。
16.一种装置，该装置包括：
基底；和
乙二醛交联的支化聚乙烯亚胺(BPEI)涂层，形成在所述基底的表面上；
其中所述乙二醛交联的BPEI涂层的胺与疏水部分或带负电的部分共价键合。
17.一种形成带负电的聚合物涂层的方法，该方法包括：
提供聚合物；和
用包含负Zeta电位的生物相容性部分功能化所述聚合物。
18.如权利要求17所述的方法，其中所述聚合物是羟基磷灰石或聚(3,4-亚乙二氧基噻吩)(PEDOT)。
19.如权利要求17所述的方法，其中所述生物相容性部分是羧酸基团或聚苯乙烯磺酸盐基团。
20.一种装置，包括：
可植入医疗器械；和
在所述可植入医疗器械的表面上形成的带负电涂层。
21.如权利要求20所述的装置，其中所述可植入医疗器械选自人工心脏瓣膜、左心室辅助装置、血管支架、血管移植物、假体关节、骨植入物、植入牙齿、可植入起搏器、起搏器发生器或导线、血管内线路、脑室腹腔分流器、导尿管、眼植入物、颅内植入物或皮下植入物。
22.如权利要求20所述的装置，还包括：
嵌入在所述可植入医疗器械内的电源；
其中所述带负电涂层由所述电源维持。
23.如权利要求22所述的装置，其中所述电源包括通过电极耦合到所述带负电涂层的电池或微电容器。
24.如权利要求23所述的装置，其中通过局部pH的变化或体温的升高来触发所述电源以维持所述带负电涂层。
25.如权利要求23所述的装置，其中触发所述电源以将所述带负电涂层保持一段时间，所述一段时间选自植入所述可植入医疗器械后的一段时间、局部pH变化或体温上升后的一段时间、或由通过嵌入在所述可植入医疗器械内的无线发射器从远程位置接收的控制信号所确定的一段时间。
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